Adjunctive therapies for the nonsurgical treatment of peri-implant diseases: systemic review and meta-analysis

Background Peri-implant diseases are caused by biofilms around the implant and may lead to implant failure. Non-surgical mechanical debridement with different adjunctive therapies has being applied in the treatment of peri-implant diseases. This systematic review aims to figure out whether one adjunctive therapy is superior to any other. Methods Two independent authors screened the literature via the MEDLINE and Cochrane Library. Only clinical randomized controlled trials (RCTs) that compared the efficacy of adjunctive therapies in the treatment of experimental peri-implant mucositis with nonsurgical mechanical debridement (MD) were included in this review. The studies selected were published before February 2020. Comparisons of clinical outcomes were estimated using meta-analysis Results: A total of thirty-one RCTs met the inclusion criteria. The following adjunctive interventions were compared in the included studies: modifying the prosthesis; air abrasive; Er:YAG laser; diode laser; photodynamic therapy; local antibiotics; system antibiotics; probiotics; enamel matrix derivative. Follow-up ranged from 3 months to 1 years. Statistically significant difference was observed between MD with photodynamic therapy and MD alone at 3 months follow-up (P < 0.01). There is no statistical difference between MD with chlorhexidine and MD alone at 3 months follow-up (P = 0.61), so is MD with probiotics and MD alone (P = 0.47), and so is systemic antibiotics and MD alone (P = 0.96). Conclusion.At present, we do not know which non-surgical intervention is superior to any other, and for the interventions having similar degrees of effectiveness we do not know which one has less side effects, is simpler and cheaper to use. It is necessary to conduct well-designed RCTs with longer follow-ups to assess the accurate effectiveness of therapies.


Abstract
Background Peri-implant diseases are caused by biofilms around the implant and may lead to implant failure. Non-surgical mechanical debridement with different adjunctive therapies has being applied in the treatment of peri-implant diseases. This systematic review aims to figure out whether one adjunctive therapy is superior to any other.
Methods Two independent authors screened the literature via the MEDLINE and Cochrane Library. Only clinical randomized controlled trials (RCTs) that compared the efficacy of adjunctive therapies in the treatment of experimental peri-implant mucositis with nonsurgical mechanical debridement (MD) were included in this review. The studies selected were published before February 2020. Comparisons of clinical outcomes were estimated using meta-analysis Results: A total of thirty-one RCTs met the inclusion criteria. The following adjunctive interventions were compared in the included studies: modifying the prosthesis; air abrasive; Er:YAG laser; diode laser; photodynamic therapy; local antibiotics; system antibiotics; probiotics; enamel matrix derivative. Follow-up ranged from 3 months to 1 years. Statistically significant difference was observed between MD with photodynamic therapy and MD alone at 3 months follow-up (P < 0.01). There is no statistical difference between MD with chlorhexidine and MD alone at 3 months follow-up (P = 0.61), so is MD with probiotics and MD alone (P = 0.47), and so is systemic antibiotics and MD alone (P = 0.96). Conclusion.At present, we do not know which non-surgical intervention is superior to any other, and for the interventions having similar degrees of effectiveness we do not know which one has less side effects, is simpler and cheaper to use. It is necessary to conduct well-designed RCTs with longer follow-ups to assess the accurate effectiveness of therapies. Background Peri-implant diseases include Peri-implant mucositis and peri-implantitis. Peri-implant mucositis is a reversible inflammatory response of the mucosa adjacent to the implant without bone loss. Peri-implantitis, instead, has been defined as an inflammatory process that affects the soft tissues surrounding an osseointegrated implant in function with concomitant loss of supporting marginal bone [1,2]. Peri-implant diseases are caused by biofilms around the implant in susceptible individuals, affecting inflammation of periimplant tissues. The incidence of peri-implant diseases is not low. According to a review, peri-implant mucositis occurs in approximately 80% of patients (50% of the implant), and in 28-66% of the patients (12-40% of the implant), the disease translates into Periimplantitis [3].
Inflammation of peri-implant tissues is caused by peri-implant biofilms in susceptible individuals [4]. Decontamination of the implant surface and eradication of the biofilm and endotoxins are the major challenge in the treatment of peri-implant diseases [5].
Mechanical debridement (MD) is recognized as indispensable, basal procedure in the nonsurgical treatment. MD can improve outcomes, such as clinical attachment level (CAL) gain and pocket probing depth (PPD) reduction [6]. However, in some clinical studies, several weeks after MD, there was a recurrence of the disease in a significant percentage of patients [7,8]. The complete resolution after MD is still not frequent event.
Many literatures compared these adjunctive therapies, and the results were diverse .
There is no consensus regarding the optimal protocol for non-surgical treatment of peri-implant diseases. A systematic comparison of different adjunctive therapies for the periimplant diseases has not yet been undertaken. Henceforth, the present systematic review aims to figure out whether one adjunctive therapy of non-surgical decontamination is superior to any other.
This systematic review was designed and conducted in accordance with the guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) 2015 statement [40].

Inclusion criteria
Only clinical randomized controlled trials (RCTs) that reported adjunctive therapies for non-surgical treatment of peri-implant diseases published before February 2020 were considered eligible for inclusion in this review. No language restrictions were applied.

Exclusion criteria
Studies requiring an additional surgical technique, such as flap surgery, guided bone regeneration or any grafting procedure were excluded. Letters to the editor, reviews, cross-sectional studies, case reports, animal studies, in vivo, and ex vivo studies were also excluded.

Screening process
Searches were performed without language restrictions in MEDLINE (PubMed) and the Cochrane Library databases until February 1, 2020. For the PubMed library, the key terms Quality assessment A quality assessment of the included studies (RCTs) was done following the recommendations for systematic reviews of interventions of the Cochrane collaboration [41], focusing on the following criteria: random sequence generation and allocation concealment (both accounting for selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment. (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), or other possible causes of bias.

Data extraction and statistical analysis
Two independent reviewers (YHX & HLJ) extracted the data. Disagreements between the two reviewers were resolved following additional discussion with a third reviewer (HYY). A standardized data extraction form was used to collect the following data: 1) author, year; 2) number of patients; 3) number of implants; 4) mean age of the patients; 5) years of implant in function; 6) gender distribution; 7) smoker; 8) history of periodontitis; 9) length of follow-up; 10) whether following the CONSORT [42]; 11) adjunctive treatments; 10) clinical outcomes, including method of assessment and time intervals.. Meta-analysis was performed using the Review Manager software (Review Manager version 5.3; The Cochrane collaboration, Copenhagen, Denmark). The statistical heterogeneity among the RCTs selected for meta-analysis was assessed utilizing the DerSimonian-Laird estimate τ 2 for inter study variance. Because each clinical outcome was evaluated in a similar way, preferring smaller values, so meta-analysis could be performed together. The meta-analysis was performed to investigate on a standardized mean difference between the clinical outcomes in the groups of adjunctive therapies compared with MD. For continuous outcomes, mean differences and standard deviations were used to summarize the data for each group using mean differences and 95% CIs.

Results
The initial search yielded 1621 publications found in PubMed Library and 1460 in Cochrane Library. Four more publications were identified by manual search. After removing duplicate studies, there were 1684 publications of potential interest to screen. After excluding articles based on their titles and abstracts, 35 studies were left for full-text assessment. Following a discussion after full-text analysis, 31 studies were included for systematic review and qualitative synthesis. The process of identification of the included studies from the initial yield is described in Fig. 1. The numbers of patients, mean age, gender distribution, implant data and adjunctive treatments are listed in Table 1. Table 1 Description of included studies.   Table 2, following the recommendations [41]. The difference of the assessment results was low and the consent was reached by discussion.

Discussion
Photodynamic therapy involves interactions between a light source and a photosensitizer in an aerobic environment. This results in the generation of free oxygen radicals that damage target cells such as bacterial cells [43]. Photodynamic therapy has also been reported to kill pathogenic microbes associated with the etiology of periodontal and periimplant disease such as Aggregatibacter actinomycetemcomitans (A.
actinomycetemcomitans), Prevotella intermedia, and Porphyromonas gingivalis (P. gingivalis) [44]. MD with adjunct photodynamic therapy is more effective in reducing periimplant PPD than MD alone at 3 months following treatment (Fig. 2). However, in the longterm outcomes of MD either with or without photodynamic therapy are comparable [18].
Adjunct use of diode laser did not yield any additional positive influence on the periimplant healing compared with MD alone at 3 months or 6 months following treatment [14,45]. Two included RCTs were about the effect of Er:YAG laser (ERL) as an adjunct in the treatment of peri-implant diseases. Studies have indicated that nonsurgical periodontal treatment with an ERL significantly improve clinical outcomes as evidenced by PPD reduction and gain of CAL [46,47]. The sites treated with ERL demonstrated a mean CAL change from 5.8 ± 1 mm at baseline to 5.1 ± 1.1 mm after 6 months. Frank et al. [12] found that ERL could also reduce BOP significantly at 6 months following treatment.
Further studies are needed to compare the effectiveness of ERL modality to that of other adjunctive therapies.
A total of two included RCTs were about the effect of air abrasive as an adjunct in the treatment of peri-implant diseases [10,11]. Both found that adjunctive air abrasive treatment seemed to have a limited beneficial effect as compared with MD alone. Air abrasive devices have been shown to be a feasible treatment option in periodontal care because it has the potential to effectively erase biofilms [48]. However, professional MD can effectively remove biofilms where the instruments can reach, thus the adjunctive effect of air abrasive may be limited.
Chlorhexidine is a commonly used topical drug. As shown in Fig. 3, compared with MD alone, MD with chlorhexidine have a limited beneficial effect at 3 months following treatment. An included article reported the adjunctive effect of chloramine and found that chloramine could not improve the clinical outcomes of peri-implant diseases [31]. The effects of probiotic Lactobacillus reuteri in combination with MD were evaluated in implants with peri-implantitis, and no clinical differences between probiotic and placebo treatments were observed over time [35,36] (Fig. 4). On the contrary, minocycline microspheres as an adjunct to MD treatment of incipient peri-implantitis lesions demonstrated improvements in PPD and BI that were sustained over 6 months [28,29]. The state of the topical drugs, the concentrations of the topical drugs and the way of delivering topical drugs may affect the effectiveness of the drugs. Dental water jet rinse mixed with chlorhexidine gel might supplement the response to nonsurgical treatment for peri-implantitis lesions by reducing PPD [32]. Studies have found that repeated chlorhexidine chips application might resolve marginal peri-implant inflammation in terms of BOP better than chlorhexidine gel, and PPD was more reduced with 0.65 ± 0.40 mm [30,38]. The efficacy of a single dose is limited, repeated application of local drugs can prolong the effectiveness. However, the frequent use of antibiotics causes bacterial resistance in the subgingival biofilm [49]. There is no consensus on how to deliver topical drugs in the treatment of peri-implant diseases. Therefore, further studies are warranted.
Standardized mean difference of clinical outcomes (BOP, PPD) between group MD with systemic antibiotics treatment and group MD alone was found no significant difference from 0 (P = 0.47) (Fig. 5). So far, the studies have not provided evidence for the use of systemic antibiotics in treatment of peri-implantitis [33,34].
Tapia et al. [9] found that modifying the contour of the prostheses after mechanical debridement significantly improved the clinical outcomes of peri-implant mucositis. This conclusion was correlated to the inclusion criteria of the study, which required the included patients to have at least one implant supported restoration with an inappropriate prosthesis design or contour that made difficult oral hygiene access to the neck of the implant. Implant supported prosthesis design is important to promote accessibility to oral hygiene around implants [50], which suggests a way to treat peri-implantitis.
Enamel matrix derivatives have been employed successfully in the management of periodontal diseases and in particular bone loss associated with periodontitis [51].
Kashefimehr et al. [39] studied the effects of enamel matrix derivative on non-surgical management of peri-implant mucositis, and they found that MD in conjunction with enamel matrix derivative, air abrasive and 0.12% chlorhexidine mouthwash significantly improved BOP and PPD at 3 months following the treatment. In the group with enamel matrix derivative, PPD reduced from 5.40 ± 1.79 mm to 4.66 ± 1.95 mm. More studies are required to prove the efficacy of enamel matrix derivative in longer-terms.
After comparing different adjunctive therapies, we found that the use of ERL or repeated minocycline microspheres as an adjunct to MD treatment for peri-implantitis is better than chlorhexidine gel [12,28]. Adjunct use of photodynamic therapy was as effective as one unit-dosage of minocycline microspheres or diode laser after 6 months of follow-up [15,21,22]. The efficacy of probiotics as an adjunct to the MD treatment was better than that of systemic antibiotics in reducing PPD and mBI. Further studies are needed to compare the effectiveness of different adjunctive therapies.

Conclusion
In summary, our study compared several therapies as adjuncts to the non-surgical MD treatment of peri-implantitis lesions. Our results showed that ERL, repeated minocycline microspheres, photodynamic therapy, modifying the prosthesis had significant effects in the short term (3 months), while air abrasive, chlorhexidine gel, probiotics   Flow chart of manuscripts screened throughout the review process.